Clinical trials to treat patients with cancer using adoptively transferred T cells (1-3) or dendritic cells (DC; refs. 4-6) have shown therapeutic efficacy for patients with advanced diseases. However, the clinical responses to such immunotherapeutic approaches have been confined to a limited percentage of treated patients. Generally, bulk tumor masses with heterogeneous populations of cancer cells have been used as a source of antigen either to generate effector T cells or to prime DC vaccines. Human tumors are composed of heterogeneous tumor cell clones that differ with respect to proliferation, differentiation, and ability to initiate daughter tumors. The inability to target cancer stem cells (CSC) with current immune approaches may be a significant factor for treatment failures.
The identification of human CSCs (7-17) presents a new paradigm for the development of cancer treatments. These stem cells have been shown to be relatively resistant to conventional chemotherapeutic regimens and radiation (18, 19) and are postulated to be the cells responsible for the relapse and progression of cancers after such therapies. In an analogous fashion, the CSC phenomenon may adversely affect the development of effective immunotherapies for cancer. These therapies have involved targeting cells that express differentiated tumor antigens. However, such antigens may be selectively expressed on differentiated tumor cells. CSCs that do not express these antigens may thus escape these immunologic interventions.